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The Dual Dose-Dependent Effects of Corticosterone on Hippocampal Cell Apoptosis After Traumatic Brain Injury Depend on the Activation Ratio of Mineralocorticoid Receptors to Glucocorticoid Receptors

In our recent studies, we reported that mineralocorticoid receptor (MR) had the opposite effects of glucocorticoid receptor (GR) on neural cell survival after traumatic brain injury (TBI). However, whether short-term use of high-dose natural glucocorticoids, which are mixed agonists of both MR and G...

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Autores principales: Zhang, Bin, Yang, Mengshi, Yan, Qiongyu, Xu, Xiaojian, Niu, Fei, Dong, Jinqian, Zhuang, Yuan, Lu, Shenghua, Ge, Qianqian, Liu, Baiyun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350576/
https://www.ncbi.nlm.nih.gov/pubmed/34381366
http://dx.doi.org/10.3389/fphar.2021.713715
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author Zhang, Bin
Yang, Mengshi
Yan, Qiongyu
Xu, Xiaojian
Niu, Fei
Dong, Jinqian
Zhuang, Yuan
Lu, Shenghua
Ge, Qianqian
Liu, Baiyun
author_facet Zhang, Bin
Yang, Mengshi
Yan, Qiongyu
Xu, Xiaojian
Niu, Fei
Dong, Jinqian
Zhuang, Yuan
Lu, Shenghua
Ge, Qianqian
Liu, Baiyun
author_sort Zhang, Bin
collection PubMed
description In our recent studies, we reported that mineralocorticoid receptor (MR) had the opposite effects of glucocorticoid receptor (GR) on neural cell survival after traumatic brain injury (TBI). However, whether short-term use of high-dose natural glucocorticoids, which are mixed agonists of both MR and GR, leads to neurotoxic effects by inducing excessive GR activation is unclear, as is the threshold GR activation level and the possible signaling pathways remain unclear. In this study, we examined the dual dose-dependent effects of corticosterone (CORT) on spatial memory, hippocampal cell survival and receptor-mediated downstream signaling pathways after TBI. We found that different doses of CORT exhibited dual effects on hippocampal cell survival and rat spatial memory. Low doses of CORT (0.3 and 3 mg/kg) significantly increased MR activation, upregulated Akt/CREB/Bad phosphorylation and Bcl-2 concentration, reduced the number of apoptotic neural cells, and subsequently improved rat spatial memory. In contrast, a high dose of CORT (30 mg/kg) exerted the opposite effects by overactivating GR, upregulating P53/Bax levels, and inhibiting Erk/CREB activity. The results suggest that the neuroprotective and neurotoxic effects of endogenous GC depend on a threshold level and that a higher dose of GC, even for short-term use, should be avoided after TBI.
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spelling pubmed-83505762021-08-10 The Dual Dose-Dependent Effects of Corticosterone on Hippocampal Cell Apoptosis After Traumatic Brain Injury Depend on the Activation Ratio of Mineralocorticoid Receptors to Glucocorticoid Receptors Zhang, Bin Yang, Mengshi Yan, Qiongyu Xu, Xiaojian Niu, Fei Dong, Jinqian Zhuang, Yuan Lu, Shenghua Ge, Qianqian Liu, Baiyun Front Pharmacol Pharmacology In our recent studies, we reported that mineralocorticoid receptor (MR) had the opposite effects of glucocorticoid receptor (GR) on neural cell survival after traumatic brain injury (TBI). However, whether short-term use of high-dose natural glucocorticoids, which are mixed agonists of both MR and GR, leads to neurotoxic effects by inducing excessive GR activation is unclear, as is the threshold GR activation level and the possible signaling pathways remain unclear. In this study, we examined the dual dose-dependent effects of corticosterone (CORT) on spatial memory, hippocampal cell survival and receptor-mediated downstream signaling pathways after TBI. We found that different doses of CORT exhibited dual effects on hippocampal cell survival and rat spatial memory. Low doses of CORT (0.3 and 3 mg/kg) significantly increased MR activation, upregulated Akt/CREB/Bad phosphorylation and Bcl-2 concentration, reduced the number of apoptotic neural cells, and subsequently improved rat spatial memory. In contrast, a high dose of CORT (30 mg/kg) exerted the opposite effects by overactivating GR, upregulating P53/Bax levels, and inhibiting Erk/CREB activity. The results suggest that the neuroprotective and neurotoxic effects of endogenous GC depend on a threshold level and that a higher dose of GC, even for short-term use, should be avoided after TBI. Frontiers Media S.A. 2021-07-26 /pmc/articles/PMC8350576/ /pubmed/34381366 http://dx.doi.org/10.3389/fphar.2021.713715 Text en Copyright © 2021 Zhang, Yang, Yan, Xu, Niu, Dong, Zhuang, Lu, Ge and Liu. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Zhang, Bin
Yang, Mengshi
Yan, Qiongyu
Xu, Xiaojian
Niu, Fei
Dong, Jinqian
Zhuang, Yuan
Lu, Shenghua
Ge, Qianqian
Liu, Baiyun
The Dual Dose-Dependent Effects of Corticosterone on Hippocampal Cell Apoptosis After Traumatic Brain Injury Depend on the Activation Ratio of Mineralocorticoid Receptors to Glucocorticoid Receptors
title The Dual Dose-Dependent Effects of Corticosterone on Hippocampal Cell Apoptosis After Traumatic Brain Injury Depend on the Activation Ratio of Mineralocorticoid Receptors to Glucocorticoid Receptors
title_full The Dual Dose-Dependent Effects of Corticosterone on Hippocampal Cell Apoptosis After Traumatic Brain Injury Depend on the Activation Ratio of Mineralocorticoid Receptors to Glucocorticoid Receptors
title_fullStr The Dual Dose-Dependent Effects of Corticosterone on Hippocampal Cell Apoptosis After Traumatic Brain Injury Depend on the Activation Ratio of Mineralocorticoid Receptors to Glucocorticoid Receptors
title_full_unstemmed The Dual Dose-Dependent Effects of Corticosterone on Hippocampal Cell Apoptosis After Traumatic Brain Injury Depend on the Activation Ratio of Mineralocorticoid Receptors to Glucocorticoid Receptors
title_short The Dual Dose-Dependent Effects of Corticosterone on Hippocampal Cell Apoptosis After Traumatic Brain Injury Depend on the Activation Ratio of Mineralocorticoid Receptors to Glucocorticoid Receptors
title_sort dual dose-dependent effects of corticosterone on hippocampal cell apoptosis after traumatic brain injury depend on the activation ratio of mineralocorticoid receptors to glucocorticoid receptors
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350576/
https://www.ncbi.nlm.nih.gov/pubmed/34381366
http://dx.doi.org/10.3389/fphar.2021.713715
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